We have previously demonstrated that repeated injections of haloperidol increase the concentrations of enkephalin in the striatum and nucleus accumbens, suggesting an intimate interrelationship between enkephalinergic and dopaminergic neurons. However, measurement of enkephalin level does not reflect the dynamic change of this peptide-containing neuron. Therefore, the first objective of this project was to develop methods to measure the turnover of brain enkephalin. We tried to measure the level of mRNA coding for endephalin precursor (preproenkephalin A) as an index for the rate of biosynthesis by cell free translation or blot hybridization using cDNA clone for preproenkephalin A. The second objective was to examine the possibility whether enkephalin and other opioid peptides can be affected by another psychiatric treatment such as electroconvulsive shock (ECS). To study the modulation of opioid peptides by haloperidol and ECS, rats received daily administration of haloperidol (1 mg/kg, i.p. for 3 weeks) or ECS (150V, 1 sec. for 6-10 days) and were killed 24 h after the last administration. Repeated injections of haloperidol caused a two-fold increase in the striatal concentration of enkephalin. This increase was accompanied by a two-fold increase in the level of mRNA coding for the precursor of enkephalin. This suggests that haloperidol accelerates the turnover of enkephalin. Furthermore, this study demonstrates that long-term treatment with haloperidol affects the gene expression of the enkephalin system. This finding raises an important consideration that gene expression may be the ultimate site of action for antipsychotic drugs. Similar to haloperidol, repeated ECS also increased the brain concentration of enkephalin and level of mRNA coding for preproenkephalin A. This finding lends further credence that gene expression may be a common site of action for various psychiatric treatments. For future studies, we plan to use the newly developed cell free translation and blot hybridization methods to study the biosynthesis of enkephalin after haloperidol or ECS in greater detail. These studies should provide further information regarding the possible role of enkephalin in mediating the actions of haloperidol and ECS.